1. Field of the Invention
The invention generally relates to cancer treatment. In particular, the present invention relates to methods for preventing or treating tumor growth, including prostate cancer, using a composition comprising a combination of zinc and sulforaphane (SFN).
2. Description of the Related Art
Prostate cancer is the sixth mostly frequently diagnosed cancer in the world, the most common cancer and the second leading cause of death due to cancer in men in the United States [1,2]. In addition, prostate cancer accounts for 29% (218,890) of new cases in man and becomes the biggest killer of men over 85 years in the United States [3,4]. Conventional therapies against prostate cancer include radiation therapy and radical prostatectomy, while more than one third of these cases will develop metastases which are further targeted by androgen ablation therapy [5]. However, some of the metastases turn androgen-independent, which renders androgen ablation therapy less effective. Therefore, more research on advanced therapies is needed to obtain better anti-cancer treatments for therapeutic/clinical purposes.
Zinc, as a form of daily diet, is an essential element for functionality of about 300 enzymes, DNA stabilization and gene expression [6]. Besides, it has been estimated that up to ten percent of all mammalian proteins bind zinc for their structure maintenance and normal activities [7]. A recent study has proposed that Zinc can serve as a signaling molecule which transfers signals in two distinct stages: 1) in early signaling, released zinc from endoplasmic reticulum (ER), as a second messenger, transfers extracellular stimulus inside cells in a calcium and mitogen-activated protein kinase (MAPK) dependent manner; 2) in late signaling, zinc may induce different expression profile [8]. The so-called late zinc signaling has been confirmed in our recent studies.
It has been well established that normal human prostate gland contains the highest zinc level among the whole body. When prostate cells become malignant, there is a dramatic decrease of cellular zinc (60-70% loss) [9]. Although the specific mechanism of such decreased zinc level in prostate cancer cells is not fully understood, our previous findings indicated that decreased expression of zinc-binding protein metallothioneins (MTs) in prostate cancer may contribute to such loss of zinc levels [10]. Furthermore, we also observed that high zinc levels could be restored in the androgen-independent malignant prostate cell line, PC-3, after zinc supplementation in vitro. It is observed that zinc exposure also induces apoptosis in PC-3 cells via mitochondria-dependent pathway, in contrast zinc-induced cell apoptosis was not observed in normal prostate cell line HPR-1 cells [11-13].
Besides trace elements like zinc, many diet foods have also been largely studied for their potential effect against cancer in recent years. Epidemiologic studies continues to support that dietary intake of cruciferous vegetables (such as broccoli and cabbage) can reduce cancer risk at sites including prostate [14-16]. Accordingly, compounds hided inside these vegetables become of interest. Among those responsible for such anticancinogenic effect of these vegetables, organic isothiocyanates (ITCs) have been considered to play a major role. SFN (1-Isothiocyanato-4-methylsulfinylbutane), as a member of ITCs family, is found highly in broccoli and broccoli sprouts [17]. Generation of SFN is conducted via hydrolysis of glucosinolates by myrosinase released when these vegetables are chewed. Since its isolation, growing studies has been focused on it due to its anticarcinogenic action as a nature product from diet. Multiple mechanisms such as inhibition of phase 1 and 2 enzymes are thought to explain its effect on cancers [18]. Due to these anticarcinogenic actions of SFN, it has been used to combine with other traditional chemotherapeutic agents to generate synergistic tumor inhibitory effect. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL), for example, was used together with SFN to boost its effect against lung and liver cancers [19,20]. Therefore, SFN might be a good candidate in terms of combinational application with other anticarcinogenic regents. However, whether SFN can sensitize prostate cancer cells to zinc effect has previously not been studied or evaluated. Thus, there is a need to identify and validate combinations of SFN and other therapies which can have therapeutic applications for treating various cancers.